Multiple lines of evidence argue that host immune responses are regulated by polymorphic gene networks that are responsible for much of the variation in immune responses seen in genetically diverse populations. The primary objective of this Program is to use genetically diverse mouse models as discovery platforms to identify novel genes and expression networks that regulate immunity and/or promote protective or pathogenic immune outcomes following infection. Our goal is to identify conserved genetic networks that regulate immune responses across pathogens, organ compartments and species, providing high value therapeutic targets for broad-based intervention strategies. To effectively study how variation in polygenic regulatory networks controls immune outcomes, it is necessary to utilize genetic resources that capture large amounts of genetic diversity across the entire genome, allow repeat measures in the same population, exploit existing immune reagents/assays, and are compatible with systems genetics approaches capable of identifying multiple interacting genes. Therefore, we will use the Collaborative Cross (CC), a novel panel of reproducible, recombinant inbred (Rl) mouse lines, to identify genes and gene networks regulating the induction, kinetics, and magnitude of the innate, inflammatory or adaptive immune responses following virus infection, using West Nile Virus, influenza and severe acute respiratory coronavirus (SARS-CoV) as models. Specifically, immune phenotypes will be collected after infection and novel modeling algorithms applied to identify quantitative trait loci (QTL), expression QTL (eQTL), and transcription networks that regulate immune function within and between organs, across virus families, and across species. Causal relationships between natural genetic variation and host signaling networks will be linked with protective or pathologic immune responses and disease outcomes. Our long-term goal is to develop new, genetically defined mouse models to mechanistically dissect the role of specific polymorphic genes and sets of genes in differentially regulating targeted immune responses, including crosstalk between immune components and the development of protective or pathogenic immune responses following virus infection.